Computational Systems Biology TUM WS 2010/11 Lecture 4: Protein - - PowerPoint PPT Presentation

Computational Systems Biology

TUM WS 2010/11

Lecture 4: Protein Structure and Disorder in Complete Genomes

2010-11-11

• Dr. Arthur Dong

How To Read A Paper

Focus: Technical details or the big picture? Within the paper:

• What's the whole point, the take-home lesson?
• Why did they do what they did? (historical perspective)
• Any parts problematic and could be improved?
• Expected versus unexpected

Go beyond the paper:

• Observation – Question – Hypothesis – Investigation – Application
• What's the next obvious step?
• Can I apply the same ideas/techniques in other areas?

Turn any question into a project (and possibly a paper)!

• Catalysis:

Almost all chemical reactions in a living cell are catalyzed by protein enzymes.

• Transport:

Some proteins transports various substances, such as oxygen, ions, and so on.

• Information transfer:

For example, hormones.

Alcohol dehydrogenase

• xidizes alcohols

to aldehydes or ketones Haemoglobin carries oxygen Insulin controls the amount of sugar in the blood

Proteins are the worker molecules in a cell

Levels of Protein Structure

Secondary structures, α-helix and β-sheet, have regular hydrogen-bonding patterns.

Sometimes we don't have a choice...

Tertiary structure

6

Protein Structure in Complete Genomes 1990s – The start of complete-genome sequencing

• Sequencing and Assembly
• Gene Prediction
• Proteome – the “parts” list of all proteins (our starting point)

 H. influenzae – 1995 (bacteria)  M. jannaschii – 1996 (archaea)  S. cerevisiae – 1996 (eukarya)

Comparison of living organisms at different scales:

• At atom and amino acids level (physics and chemistry) they are all the same.
• At species level they are all different.
• Find the happy medium – molecular biology (individual proteins etc) and systems biology

(the interaction of proteins etc) 3 diverse organisms from 3 kingdoms of life Expect significant differences in their genomes – what are those? What are actually similar?

• Method – sequence analysis
• Object – protein structure
• Perspective – genome-wide, systems-level

Compare secondary structures across genomes

• The expected
• The unexpected
• Why? Possible explanations

Comparison of super-secondary structures

Protein Tertiary Structure: PDB and SCOP

• PDB – depository of all solved structures (can be multi-domain or multi-protein)
• SCOP – classification of domains/proteins by structural and evolutionary relatedness

SCOP hierarchy:

• Family: homologs (evolutionarily related, >30% sequence identity, similar function)
• Superfamily: likely homologs (low sequence identity but similar function)
• Fold:

 Similar tertiary structure – same secondary elements arranged in the same way in

space

 Difference mainly in flanking and connecting regions e.g. loops/turns  Possibly no evolutionary relation and low sequence identity

Folds across genomes Bias → Structural Genomics Ancient folds Prevalence of mixed folds

5 Most Common Folds Present in All 3 Genomes

• Similar architecture!
• Similar function (basic metabolism)
• Why are they common? (evolution, folding energy, ...)

Application: Whole-genome trees based on fold occurance

Protein Disorder

What is protein disorder?

• Not everything folds into compact 3D structure
• Abundance of “floppy”, extended regions
• Conformation ensemble rather than fixed structure

What is its function?

• Coupled binding (“induced fit” rather than “lock-and-key”)
• High specificity, low affinity (easily reversible)
• Interaction with a large number of targets

Can you predict disorder from sequence?

• Low sequence complexity
• Amino acid compositional bias

Coupling of folding to target binding

Predicted α-helices in free peptide Experimentally determined α-helices in complex

• Can provide tighter binding than similar sized, folded proteins.
• Enthalpy-Entropy compensation.
• Allows post-translational modification.

KID domain of CREB pKID bound to KIX domain

• f CBP (CREB binding

protein).

Protein Disorder in Complete Genomes Which kinds of proteins tend to be disordered?

Gene Ontology – A Unifying Vocabulary Across Organisms

Clustering of Genes – mRNA versus GO

GO: Molecular Function Un/expected?

GO: Cellular Component Consistent?

Some obvious questions:

• Are disorder conserved?
• More protein interactions?